Posaconazole commercially known as NOXAFIL is a triazole antifungal agent indicated for treatment of invasive fungal infections.
As an effective and efficient method for production of posaconazole, it is proposed that the preparation of the intermediate of posaconazole herein after termed as benzyl posaconazole represented by structural formula III:
is suitable for a large scale production, the intermediate is crystalline which leads to ready solubility of the crystalline intermediate and overall impacting on the yield of the posaconazole API.
Crystalline forms of benzyl posaconazole are reported earlier. The International patent publication WO2011158248 (A2) claims benzyl posaconazole of Form A, which is characterised by its powder X-ray diffractogram having peaks at about 2.04, 61, 12.24, 15.06, 15.73, 17.17, 17.37, 18.15, 19.42, 19.97, 24.34, 26.0 and the WO2013042138 (A3) claims crystalline benzyl posaconazole of Form M, which is characterised by its powder X-ray diffractogram having peaks at about 3.90, 5.86, 7.82, 9.82, 11.79, 12.59, 13.38, 13.74, 16.24, 16.95, 17.83, 18.90, 20.09, 21.49, 22.89, 24.93, 26.53, 27.56, 28.73, 29.88 and 34.20. In order to achieve a method for higher yields of posaconazole in large scale production it is of necessity to develop new crystalline forms of benzyl posaconazole.
The above need is addressed in the present invention via novel crystalline polymorphs B-1, B-2 & B-3 of Benzyl posaconazole. The novel polymorphs are characterised by powder X-ray diffractogram having peaks as below:
Prominent 2θ values Crystalline form B-1: 4.14, 6.85, 9.92, 15.28, 15.69, 16.59, 17.29, 17.92, 18.27, 18.91, 20.63, 19.95, 23.58, and 25.12±0.2 degrees of 2θ.
Prominent 2θ values Crystalline form B-2: 4.20, 9.27, 14.22, 15.46, 15.82, 16.45, 17.31, 19.09, 20.47, 21.18, and 24.74±0.2 degrees of 2θ
Prominent 2θ values Crystalline form B-3: 7.07, 14.49, 15.68, 16.50, 18.05, 20.13, 20.87, 22.85, and 24.42±0.2 degrees of 2θ
The typical precision of the 2-theta values of crystalline forms B-1, B-2 & B-3 are in the range of about ±0.2 degrees of 2θ.
Patent Reference 1: PCT Publication WO2011158248;
Patent Reference 2: PCT Publication WO2013042138;
The present disclosure aims to provide novel crystalline polymorphic forms of benzyl posaconazole and methods for preparation of the same at industrial scale.
The present disclosure also aims to provide an effective and efficient method for production of amorphous form of posaconazole, the one pot process using the novel crystalline forms of B-1, B-2 & B-3 benzyl posaconazole is proposed.
Processes for preparation of amorphous forms of posaconazole have been reported earlier in the art. The International patent publication WO2013042138 (A2) discloses a few one pot processes for the preparation of amorphous form of posaconazole using 5% Pd—C and 5N HCl in methanol as solvent. The WO2015059716 (A3) discloses a few processes for the preparation of amorphous form of posaconazole involving dissolving posaconazole in dichloromethane, stirring the reaction mixture, filtering the reaction mixture, adding the filtrate to methyl tertiary butyl ether (MTBE), stirring the reaction mixture, filtering the solid and then drying to get amorphous form of posaconazole. CN104370894 discloses processes for preparation of amorphous posaconazole, posaconazole dissolved in a mixed solvent of alcohols and esters, and then added drop wise to an alkane or aromatic hydrocarbon, to get amorphous posaconazole.
Patent Reference 3: PCT Publication WO2015059716 (A3);
Patent Reference 4: Chinese patent application CN104370894;
The above reported disclosures for the preparation of amorphous form of posaconazole suffers various disadvantages with respect to the yield and quality of the amorphous posaconazole. In some cases of one pot processes the use of heavy metal catalysts for the debenzylation followed by isolation of amorphous material results in rendering the higher production costs and in other disclosures involve the isolation of posaconazole solid forms followed by another step for the amorphization which again result in the increase in the production costs and time.
Nevertheless, the present invention aims to provide a process for the preparation of amorphous posaconazole which is easy to operate, suitable for industrial scale production, cost effective and high yielding.
The present disclosure also aims to provide a one pot process for the preparation of amorphous posaconazole using novel crystalline polymorphic form B-3 of benzyl posaconazole.
The method of analysis of the compounds represented in the figures as above are as below:
PXRD Analysis
About 300 mg of powder sample was taken onto the sample holder and was tightly packed on the sample holder uniformly by means of glass slide and Powder X-ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (λ=1.5406 Å) at 40 kV and 30 mA powder. X-ray diffraction patterns were collected over the 20 range 3-50° at a scan rate of 1°/min.
DSC Analysis
DSC was performed on a Mettler Toledo DSC 822e module. 4-6 mg of sample was placed in crimped but vented aluminium sample pans. The temperature range was from 30-250° C. @ 10° C./min. Samples were purged by a stream of nitrogen flowing at 80 mL/min.
IR Analysis
IR was performed on a Fisher Scientific (NICOLET-iS50-FTIR). About 5 mg of sample was spread over the region of diamond ATR sampling station and collected the sample spectrum between 4000 cm-1 to 400 cm-1 to obtain a spectrum of suitable intensity (above 60% transmission at 2000 cm-1).